Types

Direct (methacholine, histamine) – agent binds to specific receptor on the bronchial smooth muscle causing it to contract
Indirect (mannitol, AMP, hypertonic saline, etc.) – agent triggers release of mediators in airways (from mast cells/eosinophils) leading to bronchial smooth muscle contraction
- In EIB, exercise itself is considered an indirect challenge

5 breath dosimeter method of methacholine challenge may be less sensitive than tidal breathing method, because the 5 breath dosimeter method requires inhalation to TLC that may provide bronchoprotection
- Cockroft: methacholine should be inhaled by submaximal inhalations to preserve diagnostic sensitivity

Common Indications

To diagnose or exclude asthma in someone with asthma-like symptoms and normal lung function
- Borish: arguably all patients with seemingly severe, steroid-resistant asthma and with an FEV1 >70% with inconsistencies in their presentation should undergo a methacholine challenge
To determine whether asthma treatment can be weaned (ICS)
Document effects of exposure to an occupational irritant or allergen that is suspected of causing asthma symptoms

Significance of Positive Mannitol Challenge

Confirms the presence of a sufficient number of cells with a sufficient concentration of mediators and a responsive bronchial smooth muscle to those endogenously released mediators at the time of testing
Correlates well with physician diagnosis of asthma
More likely to have:
- Positive methacholine challenge and lower PC20
- EIB
- Higher FENo and more likely to have eosinophilic (steroid-responsive) asthma
  - Negative mannitol challenge may be observed in asthmatics well-controlled on medications

Significance of Positive Methacholine Challenge

The major value of methacholine challenge is the high diagnostic sensitivity and high negative predictive value providing that symptoms are clinically current (ie, within the past day or two)
- Increased responsiveness to methacholine occurs in almost all (98-100%) of patients with symptomatic asthma
- Sensitivity is decreased in Caucasians (vs. African Americans), non-atopics (vs. atopics)
Positive methacholine challenge without asthma may be due to:
- Allergic rhinitis
- Viral URI
- COPD
- CF
- Inhalation of irritants
  - Cigarette smokers
  - Swimmers
  - Occupational exposures
- Airway injury from breathing large volumes of unconditioned air (e.g. in elite cross country skiers)
- Family history of atopy (e.g. siblings of asthmatics)
- Remodeling of the airways in response to childhood asthma
ATS guideline: if the prior probability of asthma is 30-70% and the PC20 is >16 mg/mL, it may be stated with a high degree of confidence that the patient does not currently have asthma

Note: In a study of methacholine challenge safety on 88 patients with FEV1 < 60%, only 4.5% and 0% failed to return to baseline with 1 and 2 albuterol treatments